Malaria in Malawi has been recalcitrant to the interventions associated with decreased incidence in some neighboring countries. The reasons for the failure of standard prevention and control measures to reduce the burden of malaria in Malawi remain unknown. One possible component is that current interventions aim to control malaria disease but do not adequately target transmission reservoirs to interrupt the spread of infection in this highly endemic setting. Characterizing transmission from humans to mosquitoes is complex. Identifying which humans harbor gametocytes is insufficient because successful transmission involves multidimensional relationships between human and vector behaviors, and complicated human, vector, and parasite biological interactions. Few studies have attempted to fully describe and model the factors that contribute to human to mosquito transmission, yet this information is essential. Our overall goal is to identify the most important sources of malaria transmission in the human population and to apply this information to optimize the design of new strategies to target these reservoirs. We will conduct longitudinal cohort studies including molecular detection of gametocyte infection, entomological assessments, human behavior characterization and membrane feeds to: 1) systematically characterize human-to-mosquito transmission patterns to identify the important transmission reservoir group(s) for malaria in Malawi, 2) assess the impacts of current interventions on these human reservoirs, and 3) develop analytical models using these data to design and monitor targeted interventions to efficiently reduce transmission. Our previous work has shown that school-age children have the highest prevalence of infection and of infections containing gametocytes, and are more available to vectors due to relatively infrequent ITN use. We hypothesize that school-age children are the primary reservoirs of Plasmodium transmission, that current interventions fail to adequately reach this group, and that interventions targeting this group would considerably reduce the burden of malaria in Malawi. Better understanding of human-to-mosquito transmission dynamics and the transmission reservoirs of Plasmodium in Malawi will improve the design and evaluation of interventions to target the most important human reservoirs of transmission and enhance the impact of interventions. The development of evidence-based targeted interventions will aid Malawi and other high burden settings to tackle the challenge of persistent malaria.